Painful bladder disorders are characterized by urinary frequency, urgency, and debilitating pelvic pain that affect more than 1.5 million people in the United States. Estimates of the annualized cost of treatment of patients with chronic pelvic pain range up to $3 billion. Visceral pain is the most debilitating symptom, and neurological mechanisms underlying visceral pain remain largely unknown. Currently available options for controlling bladder pain are not effective in all patients. Endogenous cannabinoids (endocannabinoids) function to limit inflammatory pain, but very little is known about their function in the bladder. We have found that inflammation of the bladder stimulates release of endocannabinoids, particularly anandamide (AEA). Previous research indicates that inflammatory mediators, particularly nerve growth factor (NGF), released from inflamed tissues play an important role in sensitization of afferent nerves and development of visceral pain. This research will employ unique methodology to measure release of endocannabinoids by the bladder in response to inflammation and the effects of inhibition of fatty acid amide hydrolase (FAAH, the enzyme primarily responsible for metabolism of AEA) on bladder pain. We will further investigate the capacity of cannabinoids to inhibit sensitization of afferent dorsal root ganglia neurons by NGF using in vitro techniques, including patch clamp studies. We will also use mice that are deficient in FAAH or one of the primary cannabinoid receptors (CB1 or CB2) to test the novel hypothesis that endocannabinoids inhibit visceral pain arising from bladder inflammation and that this effect is mediated at least in part by inhibition of the effects of NGF. The long range goal is to provide improved options for treatment or prevention of bladder pain that have fewer undesirable side effects than those associate with currently-available therapeutic options. PUBLIC HEALTH RELEVANCE: Painful bladder disorders are characterized by urinary frequency, urgency, and debilitating pelvic pain that affects more than 1.5 million people in the United States at an annual cost of as much as $3 billion. The proposed research will investigate the potential for control of bladder pain by manipulation of endogenous cannabinoids produced by the body to inhibit pain by suppressing the effects of nerve growth factor (NGF), a known mediator of bladder pain.